Inhibition of sphingolipid metabolism in osteosarcoma protects against CD151-mediated tumorigenicity.
Inhibition of sphingolipid metabolism in osteosarcoma protects against CD151-mediated tumorigenicity.
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抑制骨肉瘤中的鞘脂代谢可预防 CD151 介导的致瘤性
DOI：
10.1186/s13578-022-00900-9
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发表时间：
2022-10-08
影响因子：
7.5
通讯作者：
Sun, Wei
中科院分区：
文献类型：
--
作者：
Wang, Hongsheng;Jin, Xinmeng;Zhang, Yangfeng;Wang, Zhuoying;Zhang, Tao;Xu, Jing;Shen, Jiakang;Zan, Pengfei;Sun, Mengxiong;Wang, Chongren;Hua, Yingqi;Ma, Xiaojun;Sun, Wei
骨肉瘤是最常见的原发性骨肿瘤，由于缺乏有效的分子靶向治疗，预后差。先前的研究表明，CD 151与骨肉瘤致瘤性的不同结果之间存在关联。然而，CD 151作为治疗靶点的潜力尚未得到充分探索。在此，我们对骨肉瘤进行了综合转录组学和代谢组学分析，并将鞘脂代谢确定为CD 151调节的最重要途径。CD 151主要通过SPTCL 1调节鞘脂代谢，SPTCL 1是鞘脂生物合成中的第一个限速酶。从机制上讲，CD 151的缺失增强了c-myc多聚泛素化和随后的降解。c-myc对SPTLC 1的转录激活至关重要。在功能上，鞘脂合成和SPTLC 1抑制剂myriocin，显着抑制CD 151过表达细胞的克隆生长。重要的是，在临床前患者来源的异种移植模型中，多球壳菌素选择性抑制CD 151高表达肿瘤生长。总的来说，这些数据证实了CD 151是鞘脂代谢的关键介质，并为开发基于CD 151的骨肉瘤靶向治疗提供了新的方法。
Osteosarcoma is the most common primary bone tumor, with a poor prognosis owing to the lack of efficient molecular-based targeted therapies. Previous studies have suggested an association between CD151 and distinct consequences in osteosarcoma tumorigenicity. However, the potential of CD151 as a therapeutic target has not yet been sufficiently explored. Here, we performed integrated transcriptomic and metabolomic analyses of osteosarcoma and identified sphingolipid metabolism as the top CD151-regulated pathway. CD151 regulates sphingolipid metabolism primarily through SPTCL1, the first rate-limiting enzyme in sphingolipid biosynthesis. Mechanistically, depletion of CD151 enhanced c-myc polyubiquitination and subsequent degradation. c-myc is vital for the transcriptional activation of SPTLC1. Functionally, sphingolipid synthesis and the SPTLC1 inhibitor, myriocin, significantly suppressed the clonogenic growth of CD151-overexpression cells. Importantly, myriocin selectively restrained CD151-high expression tumor growth in preclinical patient-derived xenograft models. Collectively, these data establish that CD151 is a key mediator of sphingolipid metabolism and provide a new approach to developing novel CD151-based targeted therapies for osteosarcoma.
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影响因子：
28.2
作者：
Sayles LC;Breese MR;Koehne AL;Leung SG;Lee AG;Liu HY;Spillinger A;Shah AT;Tanasa B;Straessler K;Hazard FK;Spunt SL;Marina N;Kim GE;Cho SJ;Avedian RS;Mohler DG;Kim MO;DuBois SG;Hawkins DS;Sweet-Cordero EA
通讯作者：
Sweet-Cordero EA
影响因子：
13.5
作者：
Canals, Daniel;Clarke, Christopher J.
通讯作者：
Clarke, Christopher J.
Her4 通过 c-Myc 依赖性信号轴促进癌症代谢重编程
影响因子：
9.7
作者：
Han, Jing;Zhang, Yangfeng;Cai, Zhengdong
通讯作者：
Cai, Zhengdong
影响因子：
6.5
作者：
Bhat, Vishwanath Kumble;Bernhart, Eva;Sattler, Wolfgang
通讯作者：
Sattler, Wolfgang
影响因子：
3.6
作者：
Ryland, Lindsay K.;Fox, Todd E.;Kester, Mark
通讯作者：
Kester, Mark